Publications by authors named "Rupendra Shrestha"

92 Publications

Primary Immune Response Provides Protective Efficacy against SARS-CoV-2 Reinfection.

JNMA J Nepal Med Assoc 2021 Jul 30;59(239):727-729. Epub 2021 Jul 30.

Department of Basic Sciences, Nepal Sanjivani Institute of Health Science, Dang, Nepal.

While there is absolutely no evidence to ensure recovered patients are either likely or unlikely to get reinfected. But studies in non-human primates indicate that reinfection of recovered patients is highly unlikely. It is also clear that primary immune responses or induced immunity to severe acute respiratory syndrome coronavirus 2 remain in circulation for several months and at least temporarily confer immunity to protect from reinfection. In addition, negative virus culture analysis of re-positive suggests that positive reverse transcriptase-polymerase chain reactions in recovered patients are more likely to be false-positive, or detection of genetic remnants of virus discharged from lesions of lungs or better sampling at the time of repeat analysis. However, emerging severe acute respiratory syndrome coronavirus 2 variants are likely to be causing the infections observed in some of the recovered patients.
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http://dx.doi.org/10.31729/jnma.5538DOI Listing
July 2021

An Analysis of Hospital Costs for Childhood Cancer Care.

J Natl Compr Canc Netw 2021 Aug 6. Epub 2021 Aug 6.

1GenIMPACT: Centre for Economic Impacts of Genomic Medicine, Macquarie Business School, Macquarie University, Sydney, Australia.

Background: This study used a linked dataset consisting of all childhood cancers recorded over the course of 10 years in New South Wales (NSW), Australia, to evaluate the hospital and emergency department costs (from a payer perspective) and resources used by patients with childhood cancer. We also analyzed determinants responsible for high-frequency hospital admissions, hospital length of stay (LoS), and hospital costs.

Methods: We analyzed linked data at the individual patient level for a retrospective cohort of 2,966 patients with cancer aged <18 years with a diagnosis date between 2001 and 2012 from the NSW Central Cancer Registry, Australia. We reported costs and use of hospitalization and emergency department presentation 1 year before the date of diagnosis, 1 year after diagnosis, and 2 to 5 years after diagnosis. We also examined the association between cancer types and hospital admission and hospital costs from the payer perspective. Patient characteristics associated with the frequency of hospital admissions, hospital LoS, and hospital costs were also determined using a generalized linear model.

Results: Most hospital admission costs occurred in the first year after diagnosis, accounting for >70% of hospital costs within 5 years after diagnosis. The estimated median annual cost of hospitalization in the first year after diagnosis was A$88,964 (interquartile range [IQR], A$34,399-A$163,968) for patients diagnosed at age 0 to 14 years and A$23,384 (IQR, A$5,585-A$91,565) for those diagnosed at age 15 to 17 years. Higher frequency of hospital admissions, hospital LoS, and hospital costs were significantly associated with younger age at cancer diagnosis, cancer metastases, and living in remote/disadvantaged socioeconomic areas.

Conclusions: Our study represents one of the first in Australia to include detailed hospitalization cost information for all childhood cancer cases. This study highlights the high hospital use by pediatric patients and the importance of early diagnosis. Our findings also demonstrate the health inequities experienced by patients from remote areas and the lowest socioeconomic areas.
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http://dx.doi.org/10.6004/jnccn.2020.7802DOI Listing
August 2021

Induced pluripotent stem cells and derivative photoreceptor precursors as therapeutic cells for retinal degenerations.

Ci Ji Yi Xue Za Zhi 2020 Apr-Jun;32(2):101-112. Epub 2019 Sep 30.

Institute of Medical Sciences, Tzu Chi University, Hualien, Taiwan.

The visual impairment associated with inherited retinal degeneration and age-related degeneration of photoreceptors is causing substantial challenges in finding effective therapies. However, induced pluripotent stem cell (iPSC)-derived therapeutic cells such as photoreceptor and retinal pigment epithelium (RPE) cells provide the ultimate options in the rescue of lost photoreceptors to improve the visual function in end-stage degeneration. Retinal cells derived from iPSC are therapeutic cells that could be promising in the field of cell replacement therapy and regenerative medicine. This review presents an overview of the photoreceptor degeneration, methods of iPSC generation, iPSC in retinal disease modeling, summarizes the photoreceptor differentiation protocols, and challenges remained with photoreceptor cell replacement for the treatment of retinal diseases. Thus, the burden and increased incidence of visual impairment emphasizes the need of novel therapy, where iPSC-derived photoreceptor and RPE cells proved to be promising for curing the retinal dysfunction and act as renovation in approach to improve visual function.
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http://dx.doi.org/10.4103/tcmj.tcmj_147_19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7137374PMC
September 2019

Effective Differentiation and Biological Characterization of Retinal Pigment Epithelium Derived from Human Induced Pluripotent Stem Cells.

Curr Eye Res 2020 09 3;45(9):1155-1167. Epub 2020 Feb 3.

Institute of Medical Sciences, Tzu Chi University , Hualien, Taiwan.

Purpose: Human induced pluripotent stem cells (hiPSC)-derived retinal pigment epithelium (RPE) cells are therapeutic cells that have been shown to be promising in the rescue of lost photoreceptors. In this study, we generated hiPSC from human epidermal keratinocytes and subsequently differentiated them into RPE cells to investigate their ability to influence the retinal functions of the Royal College of Surgeon (RCS) rats.

Methods: Keratinocytes were reprogrammed to hiPSC using a non-integrating Sendai reprogramming system. Established hiPSCs were differentiated into RPE cells, and complete characterization was performed. Next, the suspension of hiPSC-RPE cells was transplanted into the subretinal space of 3-week-old RCS rats (). Posttransplantation evaluations were performed using optical coherence tomography (OCT), electroretinography, and immunohistochemical analysis.

Results: The hiPSC colonies were identical to embryonic stem-like cells that revealed the expression of pluripotency markers and retention of the normal genome. These cells exhibited the ability to differentiate into an amalgam of germ layers and produce RPE cells. The differentiated RPE cells exhibited an identical pigmented morphology that expressed RPE-specific markers, such as , and . At 8 weeks of longitudinal culture, the RPE cells exhibited maximum pigmentation with phagocytotic activity. Furthermore, transplantation data showed improved retinal function till week 12 post-transplantation and a significantly higher number of rod/cone ratios in transplanted eyes compared to non-surgery control eyes.

Conclusion: hiPSC-derived RPE cells exhibited naïve RPE cell properties and functionality that provided trophic support and the transient rescue of photoreceptor cells.
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http://dx.doi.org/10.1080/02713683.2020.1722180DOI Listing
September 2020

USE OF A CONTINUOUS GLUCOSE MONITOR FOR PREOPERATIVE MONITORING AND TREATMENT OF HYPOGLYCEMIA IN A CASE OF PANCREATIC NEUROENDOCRINE TUMOR.

AACE Clin Case Rep 2019 Jul-Aug;5(4):e255-e258. Epub 2019 Jun 7.

Objective: Pancreatic neuroendocrine tumors secreting proinsulin and insulin could lead to life-threatening hypoglycemia. We aim to show this can be avoided by utilizing continuous glucose monitoring.

Methods: We describe a case of a 55-year-old female with hypoglycemia unawareness and seizures diagnosed with proinsulinoma. She utilized an intermittently scanned continuous glucose monitor (isCGM) to monitor hypoglycemia preoperatively.

Results: The patient underwent biochemical and radiographic evaluation to confirm the diagnosis of proinsulinoma. Utilizing isCGM to monitor blood glucose, she was able to prevent hypoglycemia-related seizures prior to definitive surgery.

Conclusion: In the time leading up to a definitive surgery, patients with proinsulinomas are at risk of hypoglycemic events leading to falls, seizures, and even death. isCGMs can be utilized for preoperative monitoring and treatment of hypoglycemia in these patients.
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http://dx.doi.org/10.4158/ACCR-2018-0590DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6873829PMC
June 2019

Informal caring for back pain: overlooked costs of back pain and projections to 2030.

Pain 2020 05;161(5):1012-1018

Department of Economics, Centre for Economic Impacts of Genomic Medicine (GenIMPACT), Faculty of Business and Economics, Macquarie University, Sydney, New South Wales, Australia.

This study models the economic costs of informal caring for people with back pain, using a microsimulation model, Care&WorkMOD, from 2015 to 2030. Care&WorkMOD was based on 3 national Australian Surveys of Disability, Ageing and Carers (2003, 2009, 2012) data sets for individuals aged 15 to 64 years. Estimated national income loss due to caring for people with back pain was AU$258 million in 2015, increasing to $398 million in 2030 (54% increase). Lost income tax revenue to the Australian government due to informal care of people with back pain was estimated to be AU$78 million in 2015, increasing to AU$118 million in 2030 (50% increase), and additional welfare payments were estimated to rise from $132 million in 2015 to AU$180 in 2030 (36% increase). Larger growth in lost income, compared with the increase in welfare payments, means that there would be an increasing income gap between those out of the labour force providing informal care and noncarers who are in the labour force, leading to increased inequality. Informal carers are defined as providers of informal, unpaid assistance to someone with a health condition, for at least 6 months. Informal carers of people with back pain who are out of the labour force incur substantial economic costs. Furthermore, back pain is a large economic burden on national governments. Policies addressing back pain prevention and treatment, and supporting carers, may offset government welfare expenditure, while improving the socioeconomic well-being of carers and patients.
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http://dx.doi.org/10.1097/j.pain.0000000000001788DOI Listing
May 2020

Impact of molecular testing on thyroid nodule neoplastic diagnosis, stratified by 4-cm size, in a surgical series.

Sci Rep 2019 11 28;9(1):17861. Epub 2019 Nov 28.

Department of Medicine, University of Minnesota, Minneapolis, USA.

Whether molecular testing adds diagnostic value to the evaluation of thyroid nodules 4-cm or larger is unknown. The impact of molecular testing on cytopathologic-histopathologic diagnosis of neoplasm (adenoma or malignant), stratified by nodule size
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http://dx.doi.org/10.1038/s41598-019-52581-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6883052PMC
November 2019

Generation of hiPSC line TCIERi001-A from normal human epidermal keratinocytes.

Stem Cell Res 2019 12 15;41:101590. Epub 2019 Oct 15.

Institute of Medical Sciences, Tzu Chi University, Hualien 970, Taiwan; Institute of Eye Research, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 970, Taiwan. Electronic address:

Human induced pluripotent stem cell (hiPSC) line TCIERi001-A was generated from normal human epidermal keratinocytes (NHEK) primary cell line with the nonintegrating system using Sendai reprogramming kit. Sendai particles were used to deliver the defined transcription factors that included three vector preparations, such as polycistronic KLF4-OCT3/4-SOX2, cMYC, and KLF4.
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http://dx.doi.org/10.1016/j.scr.2019.101590DOI Listing
December 2019

Indirect costs of depression and other mental and behavioural disorders for Australia from 2015 to 2030.

BJPsych Open 2019 May 3;5(3):e40. Epub 2019 May 3.

Associate Professor, University Centre for Rural Health, School of Public Health, The University of Sydney, Australia.

Background: The impact of mental disorders has been assessed in relation to longevity and quality of life; however, mental disorders also have an impact on productive life-years (PLYs).

Aims: To quantify the long-term costs of Australians aged 45-64 having lost PLYs because of mental disorders.

Method: The Survey of Disability, Ageing and Carers 2003, 2009 formed the base population of Health&WealthMOD2030 - a microsimulation model integrating output from the Static Incomes Model, the Australian Population and Policy Simulation Model, the Treasury and the Australian Burden of Disease Study.

Results: For depression, individuals incurred a loss of AU$1062 million in income in 2015, projected to increase to AU$1539 million in 2030 (45% increase). The government is projected to incur costs comprising a 22% increase in social security payments and a 45% increase in lost taxes as a result of depression through its impact on PLYs.

Conclusions: Effectiveness of mental health programmes should be judged not only in terms of healthcare use but also quality of life and economic well-being.

Declaration Of Interest: None.
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http://dx.doi.org/10.1192/bjo.2019.26DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6520529PMC
May 2019

Intellectual disability and autism: socioeconomic impacts of informal caring, projected to 2030.

Br J Psychiatry 2019 11;215(5):654-660

Senior Research Fellow, Centre for Economic Impacts of Genomic Medicine, Department of Economics, Faculty of Business and Economics, Macquarie University, Australia.

Background: Intellectual disability and autism spectrum disorder (ASD) influence the interactions of a person with their environment and generate economic and socioeconomic costs for the person, their family and society.

Aims: To estimate costs of lost workforce participation due to informal caring for people with intellectual disability or autism spectrum disorders by estimating lost income to individuals, lost taxation payments to federal government and increased welfare payments.

Method: We used a microsimulation model based on the Australian Bureau of Statistics' Surveys of Disability, Ageing and Carers (population surveys of people aged 15-64), and projected costs of caring from 2015 in 5-year intervals to 2030.

Results: The model estimated that informal carers of people with intellectual disability and/or ASD in Australia had aggregated lost income of AU$310 million, lost taxation of AU$100 million and increased welfare payments of AU$204 million in 2015. These are projected to increase to AU$432 million, AU$129 million and AU$254 million for income, taxation, and welfare respectively by 2030. The income gap of carers for people with intellectual disability and/or ASD is estimated to increase by 2030, meaning more financial stress for carers.

Conclusions: Informal carers of people with intellectual disability and/or ASD experience significant loss of income, leading to increased welfare payments and reduced taxation revenue for governments; these are all projected to increase. Strategic policies supporting informal carers wishing to return to work could improve the financial and psychological impact of having a family member with intellectual disability and/or ASD.

Declaration Of Interest: None.
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http://dx.doi.org/10.1192/bjp.2019.204DOI Listing
November 2019

Semiquantitative assessment of cytomorphologic features can predict mutation status of thyroid nodules with indeterminate cytologic diagnosis.

Hum Pathol 2019 11 19;93:81-89. Epub 2019 Aug 19.

Department of Pathology, University of Minnesota Medical Center, 420 Delaware St SE MMC 76 Mayo 8076A (Campus Delivery Code) Minneapolis, MN 55455.

Molecular diagnostics increasingly direct the management of thyroid nodules with an indeterminate cytologic diagnosis. This study was undertaken to correlate cytomorphologic features with the molecular profiles in an effort to identify features predictive of molecular aberrations. One hundred eighty-nine thyroid nodules with an indeterminate thyroid cytology diagnosis (atypia of undetermined significance, suspicious for follicular lesion, and suspicious for malignancy) with an adequate sample submitted for targeted mutation detection by polymerase chain reaction or next-generation sequencing were assessed semiquantitatively for the following cytomorphologic parameters: cellularity, Hurthle cell changes, microfollicles, nuclear elongation, nuclear grooves, nuclear enlargement, nuclear atypia, extent of atypia, and colloid. Based on this evaluation, a cumulative cytomorphologic score (CCS) and a more simplified overall atypia score (OAS) were assigned to each case. Associations among mutational status and each of the aforementioned parameters, CCS, and OAS were determined. Of the 189 nodules with indeterminate cytology, 63 (33.3%) harbored at least 1 mutation. RAS and BRAF were the most common mutations, found in 34 (18.0%) and 13 (6.9%) cases, respectively. Both CCS and OAS were highly associated with the presence of all mutations (P < .0001) and with the presence of BRAF and RAS mutations in particular (all P < .01). Semiquantitative assessment of various cytomorphologic features in indeterminate thyroid cytology cases showed a strong association of higher OAS and CCS and incidence of BRAF and RAS mutations. Using a more objective approach to thyroid cytology can potentially decrease the overall number of indeterminate diagnoses, leading to fewer repeat procedures and unnecessary surgical procedures.
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http://dx.doi.org/10.1016/j.humpath.2019.08.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6917873PMC
November 2019

Systematic Review and Meta-analysis of the Impact of Noninvasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features (NIFTP) on Cytological Diagnosis and Thyroid Cancer Prevalence.

Endocr Pathol 2019 Sep;30(3):189-200

Department of Medicine, University Minnesota, 516 Delaware St SE, Minneapolis, MN, 55455, USA.

A re-named diagnosis of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) likely impacts the prevalence of thyroid cancer and risk of malignancy in populations based on the established Bethesda System of Reporting Thyroid Cytopathology (TBSRTC). This study was done to investigate the prevalence and cytological distribution of NIFTP. PRISMA guided systematic review was done from a database search of Pubmed, EMBASE, and Medline using the search terms "non-invasive follicular thyroid neoplasm with papillary-like nuclear features", "non-invasive follicular variant of papillary carcinoma", "niftp", and "Bethesda" until November 2018. Original articles with surgically proven diagnoses of NIFTP using strict NIFTP criteria were included. Twenty-nine studies with 1563 cases of NIFTP were included. The pooled prevalence of NIFTP in cases which would be classified previously as the follicular variant of papillary thyroid cancer (FVPTC) and papillary thyroid cancer (PTC) were 43.5% (95% CI 33.5-54.0%) and 4.4% (95% CI 2.0-9.0%) respectively. The pooled TBSRTC distribution of cases diagnosed as NIFTP was: from the non-diagnostic category 3.6% (95% CI 2.4-5.3%), benign 10.0% (95% CI 7.2-13.6%), AUS/FLUS 34.2% (95% CI 28.2-40.8%), FN/SFN 22.7% (95% CI 17.2-29.4%), suspicious for malignancy 22.4% (95% CI 17.7-27.9%), and malignant 7.5% (95% CI 4.2-12.9%). While a significant reduction in FVPTC prevalence is anticipated, a modest reduction of PTC prevalence is also expected with adoption of the NIFTP terminology that would be distributed mainly among lesions classified as indeterminate thyroid nodules. Further studies are needed to identify unique clinical characteristics of these lesions preoperatively.
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http://dx.doi.org/10.1007/s12022-019-09583-4DOI Listing
September 2019

The productivity gains associated with a junk food tax and their impact on cost-effectiveness.

PLoS One 2019 22;14(7):e0220209. Epub 2019 Jul 22.

School of Medicine, Griffith University, Gold Coast, Queensland, Australia.

Objective: To estimate the productivity impacts of a policy intervention on the prevention of premature mortality due to obesity.

Methods: A simulation model of the Australian population over the period from 2003 to 2030 was developed to estimate productivity gains associated with premature deaths averted due to an obesity prevention intervention that applied a 10% tax on unhealthy foods. Outcome measures were the total working years gained, and the present value of lifetime income (PVLI) gained. Impacts were modelled over the period from 2003 to 2030. Costs are reported in 2018 Australian dollars and a 3% discount rate was applied to all future benefits.

Results: Premature deaths averted due to a junk food tax accounted for over 8,000 additional working years and a $307 million increase in PVLI. Deaths averted in men between the ages of 40 to 59, and deaths averted from ischaemic heart disease, were responsible for the largest gains.

Conclusions: The productivity gains associated with a junk food tax are substantial, accounting for almost twice the value of the estimated savings to the health care system. The results we have presented provide evidence that the adoption of a societal perspective, when compared to a health sector perspective, provides a more comprehensive estimate of the cost-effectiveness of a junk food tax.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0220209PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6645543PMC
February 2020

The indirect costs of ischemic heart disease through lost productive life years for Australia from 2015 to 2030: results from a microsimulation model.

BMC Public Health 2019 Jun 21;19(1):802. Epub 2019 Jun 21.

National Centre for Social and Economic Modelling, University of Canberra, Canberra, ACT, Australia.

Background: Most studies measure the impact of ischemic heart disease (IHD) on individuals using quality of life metrics such as disability-adjusted life-years (DALYs); however, IHD also has an enormous impact on productive life years (PLYs). The objective of this study was to project the indirect costs of IHD resulting from lost PLYs to older Australian workers (45-64 years), government, and society 2015-2030.

Methods: Nationally representative data from the Surveys of Disability, Ageing and Carers (2003, 2009) were used to develop the base population in the microsimulation model (Health&WealthMOD2030), which integrated data from established microsimulation models (STINMOD, APPSIM), Treasury's population and workforce projections, and chronic conditions trends.

Results: We projected that 6700 people aged 45-64 were out of the labour force due to IHD in 2015, increasing to 8100 in 2030 (21 increase). National costs consisted of a loss of AU$273 (US$263) million in income for people with IHD in 2015, increasing to AU$443 ($US426) million (62% increase). For the government, extra welfare payments increased from AU$106 (US$102) million in 2015 to AU$143 (US$138) million in 2030 (35% increase); and lost income tax revenue increased from AU$74 (US$71) million in 2015 to AU$117 (US$113) million in 2030 (58% increase). A loss of AU$785 (US$755) million in GDP was projected for 2015, increasing to AU$1125 (US$1082) million in 2030.

Conclusions: Significant costs of IHD through lost productivity are incurred by individuals, the government, and society. The benefits of IHD interventions include not only improved health but also potentially economic benefits as workforce capacity.
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http://dx.doi.org/10.1186/s12889-019-7086-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6588908PMC
June 2019

Thyroid nodules over 4 cm do not have higher malignancy or benign cytology false-negative rates.

Endocrine 2019 11 29;66(2):249-253. Epub 2019 May 29.

Department of Medicine, Surgery University of Minnesota, Minneapolis, MN, USA.

Purpose: Whether thyroid nodules 4 cm or larger with benign cytology carry a higher risk of malignancy, and should be managed differently than smaller nodules remains controversial. We aimed to evaluate the malignancy rate and benign cytology false-negative rate in thyroid nodules ≥4 cm compared with those <4 cm.

Methods: All thyroidectomies between January 2010 and December 2014 were reviewed. Patient demographics, preoperative sonographic nodule size, fine needle aspiration cytology (FNAC), and final surgical pathology results were compared for index nodules ≥4 vs. <4 cm.

Results: A total of 490 index nodules with preoperative FNAC were identified. A total of 137 nodules were ≥4 cm and 353 nodules were <4 cm. The prevalence of carcinoma was lower (23 vs. 53%) in nodules ≥4 vs. <4 cm (p < 0.0001). The false-negative rate of benign FNAC for ≥4 and <4 cm index nodule was 5.2% and 5.9%, respectively (p = 1.000).

Conclusions: This study shows that thyroid nodules ≥4 cm do not have a higher malignancy rate at surgery nor higher benign cytology false-negative rate than smaller nodules. Thyroid nodules over 4 cm do not require resection, to rule out malignancy, based on size alone.
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http://dx.doi.org/10.1007/s12020-019-01964-3DOI Listing
November 2019

Productivity costs of cardiovascular disease mortality across disease types and socioeconomic groups.

Open Heart 2019;6(1):e000939. Epub 2019 Feb 16.

Centre for Economic Impacts of Genomic Medicine, Macquarie University, Sydney, New South Wales, Australia.

Background: Cardiovascular disease (CVD) is the single largest contributor to global mortality. Premature mortality due to CVD results in a loss of productivity, with associated economic and policy implications that are often overlooked.

Methods: A human capital approach was adopted to project the long-term impacts of Australian CVD deaths in 2003 on labour force participation and the present value of lifetime income (PVLI) forgone. Impacts were modelled to the year 2030 and accounted for individual characteristics at the time of death including age, sex and socioeconomic status.

Results: Premature deaths due to CVD in 2003 accounted for 51 659 working years and $2.69 billion in PVLI forgone when modelled to 2030 (95% CI $2.63 billion to $2.75 billion). The labour force impacts were highest for individuals aged between 35 and 64 at the time of death, and male deaths accounted for 87% of the total PVLI loss. The most costly disease type was ischaemic heart disease, followed by stroke and inflammatory heart disease. Deaths occurring in individuals residing in the most socioeconomically disadvantaged areas at the time of death had a disproportionately large impact on the total PVLI loss.

Conclusions: This study quantifies the relative productivity costs of CVD mortality across a range of disease types and socioeconomic groups. The magnitude of these costs highlights the scope for investments in effective healthcare interventions to provide positive economic returns and may assist decision makers in allocating resources among competing priorities.
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http://dx.doi.org/10.1136/openhrt-2018-000939DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6443138PMC
February 2021

Late Response of Antiretroviral Therapy in an HIV-1-Infected Patient due to Hepatitis B and C Coinfections: The First Case Report in Nepal.

Case Rep Med 2019 11;2019:2070973. Epub 2019 Feb 11.

Sukraraj Tropical & Infectious Disease Hospital, Teku, Kathmandu, Nepal.

Aim: Dual coinfection of HCV and HBV in HIV-1-infected population is a leading cause of morbidity and mortality. Also, they share routes of HIV transmission; however, it might be associated with an independent factor like injecting drug use for HCV and unsafe sex for HBV. This case report suggests that hepatitis virus coinfection may lead to late response of antiretroviral therapy (ART) in HIV-1 patients.

Patients And Methods: A 49-year-old male patient visited for the routine follow-up investigation at the National Public Health Laboratory (NPHL), Teku, Nepal. He was an HIV-1-positive injecting drug user (IDU) co-infected with HCV and HBV. The patient was under ART as per the National HIV Testing and Treatment Guidelines 2017, Nepal. Further, serological and viral load testing was performed for confirmation and monitoring therapy, respectively.

Results: It is the first report that highlights the dual coinfection of HCV and HBV in an HIV-1 patient from Nepal. The follow-up investigation shows improved response to ART with an increase in CD4+ cells. However, detectable viral loads indicated for a late response might be due to effects of coinfections or viral interactions.

Conclusions: Dual coinfection is rare; however, it is more serious with poorly defined epidemiology and evolution in an HIV-1-infected population. Thus, universal screening of HBV or/and HCV coinfection in HIV-1-infected population requires immediate implementation for true prevalence, proper management, and early intervention.
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http://dx.doi.org/10.1155/2019/2070973DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6388324PMC
February 2019

Duration and onset of action of high dose U-500 regular insulin in severely insulin resistant subjects with type 2 diabetes.

Endocrinol Diabetes Metab 2018 Oct 10;1(4):e00041. Epub 2018 Sep 10.

Department of Medicine Division of Diabetes, Endocrinology and Metabolism University of Minnesota Minneapolis Minnesota.

Aim: Although regular human U-500 insulin (U-500) is frequently used for insulin resistant type 2 diabetics, pharmacokinetic and pharmacodynamic studies in these individuals are lacking. We set out to determine the rate of onset, duration of action and total glucose lowering effect of two doses of U-500 insulin in obese insulin resistant subjects with type 2 diabetes.

Materials And Methods: Randomized double-blind crossover study was designed to study subjects who were administered either 100 or 200 units SQ of U-500 insulin once and then were provided intravenous glucose as necessary to maintain euglycaemia.

Results: A total of 12 subjects were studied. The time during which intravenous glucose was required to maintain euglycaemia following a 200-unit dose of U-500 insulin was significantly greater than the time following a 100-unit dose. No differences were found between doses in measures related to the rate of onset or in the total amount of intravenous glucose required to maintain euglycaemia for the duration of the study.

Conclusions: The duration of action of U-500 increases when dose is increased from 100 to 200 units. Neither dose of U-500 insulin has an onset of action before 2.5 hours after administration. This suggests that U-500 should not be used as a premeal bolus insulin to lower glucose two hours after a meal and that dosing intervals might need to be extended as dose is increased to avoid hypoglycaemia.
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http://dx.doi.org/10.1002/edm2.41DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6354819PMC
October 2018

Cytomorphology of Noninvasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features and the Impact of New Nomenclature on Molecular Testing.

Med Sci (Basel) 2019 Jan 22;7(2). Epub 2019 Jan 22.

Division of Endocrinology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, GZ-6, Boston, MA 02215, USA.

The re-naming of noninvasive follicular variant papillary thyroid cancer to the apparently non-malignant, noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) impacts the prevalence of malignancy rates, thereby affecting mutation frequency in papillary thyroid cancer. Preoperative assessment of such nodules could affect management in the future. The original publications following the designation of the new nomenclature have been extensively reviewed. With the adoption of NIFTP terminology, a reduction in the follicular variant of papillary thyroid cancer (FVPTC) prevalence is anticipated, as is a modest reduction of papillary thyroid cancer (PTC) prevalence that would be distributed mainly across indeterminate thyroid nodules. Identifying NIFTP preoperatively remains challenging. mutations are predominant but the presence of V600E mutation has been observed and could indicate inclusion of the classical PTC. The histological diagnosis of NIFTP to designate low-risk encapsulated follicular variant papillary thyroid cancers (EFVPTCs) would impact malignancy rates, thereby altering the mutation prevalence. The histopathologic criteria have recently been refined with an exclusion of well-formed papillae. The preoperative identification of NIFTP using cytomorphology and gene testing remains challenging.
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http://dx.doi.org/10.3390/medsci7020015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6410294PMC
January 2019

Aberrant hiPSCs-Derived from Human Keratinocytes Differentiates into 3D Retinal Organoids that Acquire Mature Photoreceptors.

Cells 2019 01 9;8(1). Epub 2019 Jan 9.

Institute of Medical Sciences, Tzu Chi University, Hualien 970, Taiwan.

Human induced pluripotent stem cell (hiPSC)-derived three-dimensional retinal organoids are a new platform for studying the organoidogenesis. However, recurrent genomic aberration, acquired during generation of hiPSCs, limit its biomedical application and/or aberrant hiPSCs has not been evaluated for generation of differentiated derivatives, such as organoids and retinal pigment epithelium (RPE). In this study, we efficiently differentiated mosaic hiPSCs into retinal organoids containing mature photoreceptors. The feeder-free hiPSCs were generated from the human epidermal keratinocytes that were rapid in process with improved efficiency over several passages and maintained pluripotency. But, hiPSCs were cytogenetically mosaic with normal and abnormal karyotypes, while copy number variation analysis revealed the loss of chromosome 8q. Despite this abnormality, the stepwise differentiation of hiPSCs to form retinal organoids was autonomous and led to neuronal lamination. Furthermore, the use of a Notch inhibitor, DAPT, at an early timepoint from days 29⁻42 of culture improved the specification of the retinal neuron and the use of retinoic acid at days 70⁻120 led to the maturation of photoreceptors. hiPSC-derived retinal organoids acquired all subtypes of photoreceptors, such as , and . Additionally, the advanced maturation of photoreceptors was observed, revealing the development of specific sensory cilia and the formation of the outer-segment disc. This report is the first to show that hiPSCs with abnormal chromosomal content are permissive to the generation of three-dimensional retinal organoids.
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http://dx.doi.org/10.3390/cells8010036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6356277PMC
January 2019

Economic costs of informal care for people with chronic diseases in the community: Lost income, extra welfare payments, and reduced taxes in Australia in 2015-2030.

Health Soc Care Community 2019 03 30;27(2):493-501. Epub 2018 Oct 30.

The University of Sydney, University Centre for Rural Health, Lismore, NSW, Australia.

We estimated the economic costs of informal care in the community from 2015 to 2030, using an Australian microsimulation model, Care&WorkMOD. The model was based on data from three Surveys of Disability, Ageing, and Carers (SDACs) for the Australian population aged 15-64 years old. Estimated national income lost was AU$3.58 billion in 2015, increasing to $5.33 billion in 2030 (49% increase). Lost tax payments were estimated at AU$0.99 billion in 2015, increasing to AU$1.44 billion in 2030 (45% increase), and additional welfare payments were expected to rise from $1.45 billion in 2015 to AU$1.94 in 2030 (34% increase). There are substantial economic costs both to informal carers and the government due to carers being out of the labour-force to provide informal care for people with chronic diseases. Health and social policies supporting carers to remain in the labour force may allow governments to make substantial savings, while improving the economic situation of carers.
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http://dx.doi.org/10.1111/hsc.12670DOI Listing
March 2019

Role of Relative Malnutrition in Exercise Hypogonadal Male Condition.

Med Sci Sports Exerc 2019 02;51(2):234-236

Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Minnesota, Minneapolis, MN.

Objective: Exercise hypogonadal male condition is a well-recognized condition in women but much less understood in men. The aim of this case report is to highlight exercise-induced hypogonadotropic hypogonadism in a male who recovered with lifestyle modifications.

Methods: We report a case of an adolescent male who developed hypogonadotropic hypogonadism secondary to excessive exercise and malnutrition that was followed up for a year without exogenous testosterone supplementation. Informed consent was obtained from the patient for his information to be used in a manuscript submitted to a journal.

Results: An 18-yr-old adolescent male presented to the clinic with symptoms of fatigue and low endurance, low libido, and lack of morning erections. At the time of his presentation, he was running about 60 miles per week for school cross-country team in addition to cross training with kickboxing. Physical examination was remarkable for low body mass index of 19 kg·m but was otherwise normal. Biochemical workup confirmed hypogonadotropic hypogonadism and a mild pancytopenia. Other pituitary laboratory values and MRI of the brain were unremarkable. Bone marrow biopsy performed for anemia showed features consistent with malnutrition. With a working diagnosis of exercise hypogonadal male condition, he was advised to reduce the frequency and intensity of his exercise and increase calorie intake. Cell counts and testosterone levels normalized, and his symptoms resolved without any further interventions.

Conclusion: Significant reversible hypogonadism can develop after intensive and prolonged exercise. One of the mechanisms of hypogonadism in endurance athletes performing intensive exercise could be relative malnutrition. Further studies to evaluate the role of nutrition and body mass index in male endurance athletes presenting with hypogonadism are needed to identify the underlying mechanism of this condition.
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http://dx.doi.org/10.1249/MSS.0000000000001783DOI Listing
February 2019

Correction: Does genomic sequencing early in the diagnostic trajectory make a difference? A follow-up study of clinical outcomes and cost-effectiveness.

Genet Med 2019 02;21(2):516

Murdoch Children's Research Institute, Melbourne, Australia.

The original PDF version of this Article omitted to list Clara L Gaff as a corresponding author and the affiliations were incorrectly labelled as Present Addresses. Furthermore, Tables 1 and 2 have been updated to clarify that the Australian dollar is used for the values. These errors have now been corrected in the PDF and HTML versions of the Article.
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http://dx.doi.org/10.1038/s41436-018-0078-5DOI Listing
February 2019

The long-term economic impacts of arthritis through lost productive life years: results from an Australian microsimulation model.

BMC Public Health 2018 05 24;18(1):654. Epub 2018 May 24.

University Centre for Rural Health, School of Public Health, The University of Sydney, Lismore, NSW, Australia.

Background: While the direct (medical) costs of arthritis are regularly reported in cost of illness studies, the 'true' cost to indivdiuals and goverment requires the calculation of the indirect costs as well including lost productivity due to ill-health.

Methods: Respondents aged 45-64 in the ABS Survey of Disability, Ageing and Carers 2003, 2009 formed the base population. We projected the indirect costs of arthritis using Health&WealthMOD2030 - Australia's first microsimulation model on the long-term impacts of ill-health in older workers - which incorporated outputs from established microsimulation models (STINMOD and APPSIM), population and labour force projections from Treasury, and chronic conditions trends for Australia. All costs of arthritis were expressed in real 2013 Australian dollars, adjusted for inflation over time.

Results: We estimated there are 54,000 people aged 45-64 with lost PLYs due to arthritis in 2015, increasing to 61,000 in 2030 (13% increase). In 2015, people with lost PLYs are estimated to receive AU$706.12 less in total income and AU$311.67 more in welfare payments per week than full-time workers without arthritis, and pay no income tax on average. National costs include an estimated loss of AU$1.5 billion in annual income in 2015, increasing to AU$2.4 billion in 2030 (59% increase). Lost annual taxation revenue was projected to increase from AU$0.4 billion in 2015 to $0.5 billion in 2030 (56% increase). We projected a loss in GDP of AU$6.2 billion in 2015, increasing to AU$8.2 billion in 2030.

Conclusions: Significant costs of arthritis through lost PLYs are incurred by individuals and government. The effectiveness of arthritis interventions should be judged not only on healthcare use but quality of life and economic wellbeing.
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http://dx.doi.org/10.1186/s12889-018-5509-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5968603PMC
May 2018

Does genomic sequencing early in the diagnostic trajectory make a difference? A follow-up study of clinical outcomes and cost-effectiveness.

Genet Med 2019 01 15;21(1):173-180. Epub 2018 May 15.

Murdoch Children's Research Institute, Melbourne, Australia.

Purpose: To systematically investigate the longer-term clinical and health economic impacts of genomic sequencing for rare-disease diagnoses.

Methods: We collected information on continuing diagnostic investigation, changes in management, cascade testing, and parental reproductive outcomes in 80 infants who underwent singleton whole-exome sequencing (WES).

Results: The median duration of follow-up following result disclosure was 473 days. Changes in clinical management due to diagnostic WES results led to a cost saving of AU$1,578 per quality-adjusted life year gained, without increased hospital service use. Uninformative WES results contributed to the diagnosis of non-Mendelian conditions in seven infants. Further usual diagnostic investigations in those with ongoing suspicion of a genetic condition yielded no new diagnoses, while WES data reanalysis yielded four. Reanalysis at 18 months was more cost-effective than every 6 months. The parents of diagnosed children had eight more ongoing pregnancies than those without a diagnosis. Taking the costs and benefits of cascade testing and reproductive service use into account, there was an additional cost of AU$8,118 per quality-adjusted life year gained due to genomic sequencing.

Conclusion: These data strengthen the case for the early use of genomic testing in the diagnostic trajectory, and can guide laboratory policy on periodic WES data reanalysis.
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http://dx.doi.org/10.1038/s41436-018-0006-8DOI Listing
January 2019

The economic impacts of using adalimumab (Humira ) for reducing pain in people with ankylosing spondylitis: A microsimulation study for Australia.

Int J Rheum Dis 2018 May 3;21(5):1106-1113. Epub 2018 Apr 3.

Faculty of Pharmacy, Charles Perkins Centre, The University of Sydney, New South Wales, Australia.

Aim: The onset and progression of ankylosing spondylitis (AS) usually occurs during the life stage when individuals are more likely to be working and receiving an income, but little is known about the effects of interventions that reduce pain and improve the economic circumstances of patients out of the labour force due to AS. This study evaluates the economic benefits of pain reduction among people aged 19-64 with AS using adalimumab (Humira ) from the patient and governmental perspectives.

Methods: We estimated the benefits of adalimumab for reducing pain in people aged 19-64 with AS in terms of labor force participation and earnings, and to the Australian Government in terms of income tax revenue and welfare payments using economic simulation. The simulation model integrated data from the Adalimumab Trial Evaluating Long-Term Safety and Efficacy for Ankylosing Spondylitis (ATLAS), the Household Income and Labour Dynamics in Australia (HILDA) Survey - Wave 10, and Static Incomes Model (STINMOD). All benefits are expressed in 2014 real Australian dollars.

Results: We estimated an additional 131 people aged 19-64 with AS (111 males, 20 females) would be in the labour force after using adalimumab for 24 weeks. National benefits consisted of an increase in annual earnings of AU$7.4 million for patients through increased labour force participation, savings of $2 million in annual welfare payments, and an increase of $1.3 million in income tax revenue in 2014 (after 24 weeks).

Conclusion: Adalimumab therapy generates substantial economic benefits in addition to health benefits for individuals, and savings for government.
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http://dx.doi.org/10.1111/1756-185X.13277DOI Listing
May 2018

Whole-exome sequencing reanalysis at 12 months boosts diagnosis and is cost-effective when applied early in Mendelian disorders.

Genet Med 2018 12 29;20(12):1564-1574. Epub 2018 Mar 29.

Randwick Genetics, NSW Health Pathology, Prince of Wales Hospital, Randwick, New South Wales, Australia.

Purpose: Whole-exome sequencing (WES) has revolutionized Mendelian diagnostics, however, there is no consensus on the timing of data review in undiagnosed individuals and only preliminary data on the cost-effectiveness of this technology. We aimed to assess the utility of WES data reanalysis for diagnosis in Mendelian disorders and to analyze the cost-effectiveness of this technology compared with a traditional diagnostic pathway.

Methods: WES was applied to a cohort of 54 patients from 37 families with a variety of Mendelian disorders to identify the genetic etiology. Reanalysis was performed after 12 months with an improved WES diagnostic pipeline. A comparison was made between costs of a modeled WES pathway and a traditional diagnostic pathway in a cohort with intellectual disability (ID).

Results: Reanalysis of WES data at 12 months improved diagnostic success from 30 to 41% due to interim publication of disease genes, expanded phenotype data from referrer, and an improved bioinformatics pipeline. Cost analysis on the ID cohort showed average cost savings of US$586 (AU$782) for each additional diagnosis.

Conclusion: Early application of WES in Mendelian disorders is cost-effective and reanalysis of an undiagnosed individual at a 12-month time point increases total diagnoses by 11%.
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http://dx.doi.org/10.1038/gim.2018.39DOI Listing
December 2018

LETTER TO THE EDITOR.

Endocr Pract 2018 02;24(2):231-232

Harvard Medical School, Division of Endocrinology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, E-mail:

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http://dx.doi.org/10.4158/1934-2403-24.2.231DOI Listing
February 2018

Integrating exome sequencing into a diagnostic pathway for epileptic encephalopathy: Evidence of clinical utility and cost effectiveness.

Mol Genet Genomic Med 2018 03 4;6(2):186-199. Epub 2018 Jan 4.

Sydney Children's Hospital, Randwick, NSW, Australia.

Background: Epileptic encephalopathies are a devastating group of neurological conditions in which etiological diagnosis can alter management and clinical outcome. Exome sequencing and gene panel testing can improve diagnostic yield but there is no cost-effectiveness analysis of their use or consensus on how to best integrate these tests into clinical diagnostic pathways.

Methods: We conducted a retrospective cost-effectiveness study comparing trio exome sequencing with a standard diagnostic approach, for a well-phenotyped cohort of 32 patients with epileptic encephalopathy, who remained undiagnosed after "first-tier" testing. Sensitivity analysis was included with a range of commercial exome and multigene panels.

Results: The diagnostic yield was higher for the exome sequencing (16/32; 50%) than the standard arm (2/32; 6.2%). The trio exome sequencing pathway was cost-effective compared to the standard diagnostic pathway with a cost saving of AU$5,236 (95% confidence intervals $2,482; $9,784) per additional diagnosis; the standard pathway cost approximately 10 times more per diagnosis. Sensitivity analysis demonstrated that the majority of commercial exome sequencing and multigene panels studied were also cost-effective. The clinical utility of all diagnoses was reported.

Conclusion: Our study supports the integration of exome sequencing and gene panel testing into the diagnostic pathway for epileptic encephalopathy, both in terms of cost effectiveness and clinical utility. We propose a diagnostic pathway that integrates initial rapid screening for treatable causes and comprehensive genomic screening. This study has important implications for health policy and public funding for epileptic encephalopathy and other neurological conditions.
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http://dx.doi.org/10.1002/mgg3.355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5902395PMC
March 2018

Cost-effectiveness of massively parallel sequencing for diagnosis of paediatric muscle diseases.

NPJ Genom Med 2017 3;2. Epub 2017 Mar 3.

Institute for Neuroscience and Muscle Research, Kids Research Institute, Children's Hospital at Westmead, Sydney, NSW, Australia.

Childhood-onset muscle disorders are genetically heterogeneous. Diagnostic workup has traditionally included muscle biopsy, protein-based studies of muscle specimens, and candidate gene sequencing. High throughput or massively parallel sequencing is transforming the approach to diagnosis of rare diseases; however, evidence for cost-effectiveness is lacking. Patients presenting with suspected congenital muscular dystrophy or nemaline myopathy were ascertained over a 15-year period. Patients were investigated using traditional diagnostic approaches. Undiagnosed patients were investigated using either massively parallel sequencing of a panel of neuromuscular disease genes panel, or whole exome sequencing. Cost data were collected for all diagnostic investigations. The diagnostic yield and cost effectiveness of a molecular approach to diagnosis, prior to muscle biopsy, were compared with the traditional approach. Fifty-six patients were analysed. Compared with the traditional invasive muscle biopsy approach, both the neuromuscular disease panel and whole exome sequencing had significantly increased diagnostic yields (from 46 to 75% for the neuromuscular disease panel, and 79% for whole exome sequencing), and reduced the cost per diagnosis from USD$16,495 (95% CI: $12,413-$22,994) to USD$3706 (95% CI: $3086-$4453) for the neuromuscular disease panel and USD $5646 (95% CI: $4501-$7078) for whole exome sequencing. The neuromuscular disease panel was the most cost-effective, saving USD$17,075 (95% CI: $10,654-$30,064) per additional diagnosis, over the traditional diagnostic pathway. Whole exome sequencing saved USD$10,024 (95% CI: $5795-$17,135) per additional diagnosis. This study demonstrates the cost-effectiveness of investigation using massively parallel sequencing technologies in paediatric muscle disease. The findings emphasise the value of implementing these technologies in clinical practice, with particular application for diagnosis of Mendelian diseases, and provide evidence crucial for government subsidy and equitable access.
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http://dx.doi.org/10.1038/s41525-017-0006-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5677979PMC
March 2017
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